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Assessment of coagulation potential of concomitantly used factor VIII concentrates in hemophilia A patients with emicizumab prophylaxis (CAGUYAMA Study)

CAGUYAMA Study (CAGUYAMA Study)

100

Baseline background characteristics for the full study population and the efficacy analysis population (participants in the study who had events only, Full Analysis Set; FAS) are shown below (summarized as median [minimum, maximum] or frequency (%)). Full study population N=100 Age: 30.5 [4, 73]. History of emicizumab use (months): 30.0[0, 66] Hemophilia A severity: Mild (>=5%): 2 (2.0%) Moderate (1-5%): 10 (10.0%) Severe (<1%): 88 (88.0%) FVIII product use to date CROSS EIGHT MC: 14(14.0%) Kogenate-FS: 10(10.0%) Kovaltry: 11(11.0%) ADVATE: 40(40.0%) ADYNOVATE: 19(19.0%) NovoEight: 7(7.0%) ELOCTATE: 36(36.0%) AFSTYLA: 3(3.0%) Others: 7(7.0%) Recconate: 3(3.0%) Jivi: 4(4.0%) NUWIQ: 1(1.0%) CROSS EIGHT M: 1(1.0%) Kogenate: 1(1.0%) Conco-eight: 1(1.0%) Hemate-P: 1(1.0%) Efficacy analysis population (FAS) N=24 Age: 34.5[4, 73] History of emicizumab use (months): 27.0[0, 53] Hemophilia A severity: Mild (>=5%): 0 (0.0%) Moderate (1-5%): 2 (8.3%) Severe (<1%): 22 (91.7%) FVIII product use to date CROSS EIGHT MC: 4(16.7%) Kogenate-FS: 3(12.5%) Kovaltry: 4(16.7%) ADVATE: 13(54.2%) ADYNOVATE: 7(29.2%) NovoEight: 2(8.3%) ELOCTATE: 7(29.2%) AFSTYLA: 1(4.2%) Others: 2(8.3%) Recconate: 1(4.2%) Jivi: 2(8.3%)

2022/01/17: Date of first participant enrollment 2022/03/10: Date of first event 2024/07/30: Date of last event 2024/12/19: Date of last visit

In the safety analysis population (overall study participant population, N=100), the incidence of adverse events after study enrollment was 5.0%(5 case, 5 events), and there were 0 events for which a causal relationship to the study drug (emicizumab) could not be ruled out. The incidence of serious adverse events was 5.0% (5 cases, 5 events). Details of serious adverse events are given below. no AESI were occurred. -Serious adverse events Intra-abdominal haemorrhage (1 case, 1.0%; no causal relationship) Febrile convulsion (1 case, 1.0%; no causal relationship) COVID-19 (1 case, 1.0%; no causal relationship) Femur fracture (1 case, 1.0%; no causal relationship) Femoral neck fracture (1 case, 1.0%; no causal relationship)

Analyses for bleeding events included only firstever events for each study participant (First Event Analysis Set; FEAS). The analysis using the data collected at the time of registration was conducted on the full study population . -Primary endpoint The mean [95% confidence interval (95%CI)] of the "Maximum coagulation velocity by modified clot waveform analysis after administration of FVIII product" ranged from 5.5[5.2 to 5.9] (before administration) to 7.6[7.2 to 8.0] (after administration). Relative to the Nara Medical University institutional reference value (0%, 3.97; 100%, 7.83), the relative values ranged from 40.7%[32.0% to 49.5%] (before administration) to 93.8%[84.4% to 103.2%] (after administration). -Secondary endpoint 1. Evaluation of hemostasis status in clinical symptoms Hemostatic conditions were "effective" in 24 patients (100.0%, including 11 cases of hemorrhage due to rupture and 13 cases of surgery); "ineffective", "exacerbation", and "difficult to determine" were all 0 cases. 2. Coagulation parameters before and after administration of FVIII product with and without addition of anti-emicizumab antibody The mean [95%CI] of the maximum coagulation velocity with anti-emicizumab antibody addition ranged from 4.1[3.9 to 4.4] (before administration) to 7.1[6.7 to 7.4] (after administration). The relative response rate was 3.2%[-1.6% to 8.1%] (before administration) to 78.6%[70.3% to 86.8%] (after administration) when relative to the institutional reference value of Nara Medical University. (Nara Medical University institutional reference value and without anti-emicizumab antibody addition results are the same as for the primary endpoint). 3. Coagulation parameters at the time of registration and before administration of FVIII product with or without addition of antiemicizumab antibody The mean [95%CI] of the maximum coagulation velocity at enrollment ranged from 5.4[5.3 to 5.6] (without anti-emicizumab antibody) and 4.0[3.9 to 4.1] (with anti-emicizumab antibody). The relative response rate was 0.8%[-1.8% to 3.4%] (without anti-emicizumab antibody) and 37.0%[34.5% to 42.2%] (with anti-emicizumab antibody). (Nara Medical University institutional reference value is same as for the primary endpoint and before administration of FVIII product results are the same as for the secondary endpoint 2). 4. General coagulation parameters and blood level of emicizumab in blood samples before and after administration of FVIII product The mean values [95% confidence intervals] for each parameter are as follows; Emicizumab blood concentration (mcg/mL) Pre: 48.9[41.7 to 56.1] Post: 50.5[43.1 to 58.0] Platelet (by 10^5 / mcL) Pre: 27.0[24.1 to 29.9] Post: 27.0[24.2 to 29.9] FDP(mcg/mL) Pre: 2.4[1.9 to 2.9] Post: 2.2[1.7 to 2.8] D-Dimer(mcg/mL) Pre: 0.4[0.2 to 0.6] Post: 0.4[0.2 to 0.6] 5. General coagulation parameters and blood level of emicizumab in blood samples at the time of registration and before administration of FVIII product The mean values [95% confidence intervals] for each parameter at enrolment are as follows; Emicizumab blood concentration (mcg/mL) 51.2[47.7 to 54.0] Platelet (by 10^5 / mcL) 26.9[25.5 to 28.2] FDP(mcg/mL) 2.2[2.0 to 2.4] D-Dimer(mcg/mL) 0.3[0.2 to 0.4]

In PwHA receiving emicizumab, FVIII at 30 +- 5 U/kg was found to be both effective and safe for managing breakthrough bleeding and for haemostasis during surgical procedures.

Sept. 30, 2025

Yes

Data availability statements: The individual de-identified participant data will be shared upon reasonable request to the Contact for Scientific Queries. The data will become available from the end of the study until 5 years. Data sharing will be limited to requests from non-profit investigators and will be provided as electronic records.

https://jrct.mhlw.go.jp/latest-detail/jRCTs051210137

Nogami Keiji

Nara Medical University Hospital

840 Shijo-Cho, Kashihara, Nara,Japan

roc-noga@naramed-u.ac.jp

Takeyama Masahiro

Nara Medical University Hospital

840 Shijo-Cho, Kashihara, Nara,Japan

+81-744-22-3051

mtake@naramed-u.ac.jp

Complete

Dec. 20, 2021

Interventional

non-randomized controlled trial

open(masking not used)

active control

single assignment

treatment purpose

1)Congenital hemophilia A patients without inhibitor over 4 years old
2)Patients receiving emicizumab 5 times or more based on the latest package insert
3)Patients who have received sufficient explanation about the contents of this clinical study, and have obtained written consent from the study patients or their legal guardian
4)Patients who can comply with the planned procedure in this clinical study

1)Patients who have difficulty in regular visits and/or visits at the events
2)Patients with other diseases with abnormal liver function or platelet count (AST and/or ALT are 5 times or more of the normal upper limit. Platelet count<100,000/microliter)
3)Patients with extremely difficult blood collection
4)Patients who are judged by the investigator to be inappropriate for some reasons

Male

Hemophilia A without inhibitor

Selection and dosage of factor VIII formulations in rupture hemorrhage or hemostasis management during surgery

Maximum coagulation velocity by modified clot waveform analysis after administration of FVIII product

1)Evaluation of hemostasis status in clinical symptoms
2)Coagulation parameters before and after administration of FVIII product with and without addition of anti-emicizumab antibody
3)Coagulation parameters at the time of registration and before administration of FVIII product with or without addition of anti-emicizumab antibody
4)General coagulation parameters and blood level of emicizumab in blood samples before and after administration of FVIII product
5)General coagulation parameters and blood level of emicizumab in blood samples at the time of registration and before administration of FVIII product

+81-744-29-8835

Oct. 25, 2021

none